Entecavir, [1-S-(1α,3α,4β)]-2-amino-1,9-dihydro-9-[4-hydroxy-3-(hydroxymethyl)-2-methylenecyclopentyl]-6H-purin-6-one, is an antiviral agent being used for treating hepatitis B virus infection, whose three dimensional structure is composed of a cyclopentane having purine at 1S-position, exomethylene at 2-position, hydroxymethyl at 3R-position, and hydroxy at 4S-position. Entecavir is activated as entecavir triphosphate form by phosphorylation, and exhibits a treatment effect for hepatitis B. Commercially available therapeutic agents for hepatitis B contain 0.5 mg or 1 mg entecavir anhydride per unit dose.
Entecavir has moisture solubility of 2.4 mg/ml at pH 7.9, 25° C. (room temperature), and shows low stability to moisture because it is hydrolyzed in the presence of moisture. Hydrolysis of entecavir leads to reduction of therapeutic effect, and therefore, it is necessary to secure moisture-stability of entecavir.
In the case of a drug showing low moisture-stability, for blocking contact with moisture commonly present outside of a preparation, methods such as moisture-proof coating or sealing for preservation and the like are used, and methods such as minimizing moisture content in a preparation or replacing with other materials (for example, glycerin, propylene glycol, alcohol and the like) and the like are also used.
However, in the case of a pharmaceutical preparation which should contains a certain content or more of moisture in a preparation, as a pharmaceutical preparation containing entecavir, a method for enhancing stability to moisture contained in the preparation in addition to block moisture outside of the preparation.